US20080194598A1 - Pyrimidine Carboxylic Acid Derivatives and Use Thereof - Google Patents
Pyrimidine Carboxylic Acid Derivatives and Use Thereof Download PDFInfo
- Publication number
- US20080194598A1 US20080194598A1 US11/886,289 US88628906A US2008194598A1 US 20080194598 A1 US20080194598 A1 US 20080194598A1 US 88628906 A US88628906 A US 88628906A US 2008194598 A1 US2008194598 A1 US 2008194598A1
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- US
- United States
- Prior art keywords
- alkyl
- formula
- alkoxy
- compound
- cyano
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
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- FNIWQASUVMMYGX-UHFFFAOYSA-N N=C(N)C1=CC=C(F)C(F)=C1 Chemical compound N=C(N)C1=CC=C(F)C(F)=C1 FNIWQASUVMMYGX-UHFFFAOYSA-N 0.000 description 1
- OOIWZCIYNAWTKJ-UHFFFAOYSA-N O=C(O)C1=C(OC2=C(Cl)C(Cl)=CC=C2)N=C(C2=CC=CC=C2)N=C1 Chemical compound O=C(O)C1=C(OC2=C(Cl)C(Cl)=CC=C2)N=C(C2=CC=CC=C2)N=C1 OOIWZCIYNAWTKJ-UHFFFAOYSA-N 0.000 description 1
- KEIDAINLIAVULD-UHFFFAOYSA-N O=C(O)C1=C(OC2=C(Cl)C=CC=C2)N=C(C2=CC=C(F)C(F)=C2)N=C1 Chemical compound O=C(O)C1=C(OC2=C(Cl)C=CC=C2)N=C(C2=CC=C(F)C(F)=C2)N=C1 KEIDAINLIAVULD-UHFFFAOYSA-N 0.000 description 1
- JJWINGKWZKPQJM-UHFFFAOYSA-N O=C(O)C1=C(OC2=C(F)C=CC(F)=C2)N=C(C2=CC=CC=C2)N=C1 Chemical compound O=C(O)C1=C(OC2=C(F)C=CC(F)=C2)N=C(C2=CC=CC=C2)N=C1 JJWINGKWZKPQJM-UHFFFAOYSA-N 0.000 description 1
- VRICOVYXHPULSM-UHFFFAOYSA-N O=C(O)C1=C(OC2=CC(C(F)(F)F)=CC=C2Cl)N=C(C2=CC=CC=C2)N=C1 Chemical compound O=C(O)C1=C(OC2=CC(C(F)(F)F)=CC=C2Cl)N=C(C2=CC=CC=C2)N=C1 VRICOVYXHPULSM-UHFFFAOYSA-N 0.000 description 1
- FZWCOQHVCJQFSQ-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)N=C1OC1=C(Cl)C=CC(Cl)=C1 Chemical compound O=C(O)C1=CN=C(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)N=C1OC1=C(Cl)C=CC(Cl)=C1 FZWCOQHVCJQFSQ-UHFFFAOYSA-N 0.000 description 1
- UDMJFEZKKVOXKU-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)N=C1OC1=C(Cl)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC(C(F)(F)F)=CC(C(F)(F)F)=C2)N=C1OC1=C(Cl)C=CC=C1 UDMJFEZKKVOXKU-UHFFFAOYSA-N 0.000 description 1
- DIEGAGJUPJAEKW-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=C(C(F)(F)F)C(F)=C2)N=C1OC1=C(Cl)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=C(C(F)(F)F)C(F)=C2)N=C1OC1=C(Cl)C=CC=C1 DIEGAGJUPJAEKW-UHFFFAOYSA-N 0.000 description 1
- FHVNCVAREODGAV-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=C(F)C=C2)N=C1OC1=C(Cl)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=C(F)C=C2)N=C1OC1=C(Cl)C=CC=C1 FHVNCVAREODGAV-UHFFFAOYSA-N 0.000 description 1
- FSESUBCNSPCGFM-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=CC(F)=C2)N=C1OC1=C(Cl)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=CC(F)=C2)N=C1OC1=C(Cl)C=CC=C1 FSESUBCNSPCGFM-UHFFFAOYSA-N 0.000 description 1
- MGDQSOJZANHDQI-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(Br)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(Br)C=CC=C1 MGDQSOJZANHDQI-UHFFFAOYSA-N 0.000 description 1
- MJDHNKWKAUHBNL-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(Cl)C=CC(Cl)=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(Cl)C=CC(Cl)=C1 MJDHNKWKAUHBNL-UHFFFAOYSA-N 0.000 description 1
- OUWLOUPCMRYBOD-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(Cl)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(Cl)C=CC=C1 OUWLOUPCMRYBOD-UHFFFAOYSA-N 0.000 description 1
- LVAGVIMFCGRRQP-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(F)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=CC=C2)N=C1OC1=C(F)C=CC=C1 LVAGVIMFCGRRQP-UHFFFAOYSA-N 0.000 description 1
- DVIKIUXSTAWLBR-UHFFFAOYSA-N O=C(O)C1=CN=C(C2=CC=CC=C2F)N=C1OC1=C(Cl)C=CC=C1 Chemical compound O=C(O)C1=CN=C(C2=CC=CC=C2F)N=C1OC1=C(Cl)C=CC=C1 DVIKIUXSTAWLBR-UHFFFAOYSA-N 0.000 description 1
- CSUZKPAQCFAMTO-UHFFFAOYSA-N [C-]#[N+]C1=CC(OC2=NC(C3=CC=CC=C3)=NC=C2C(=O)O)=C(C)C=C1 Chemical compound [C-]#[N+]C1=CC(OC2=NC(C3=CC=CC=C3)=NC=C2C(=O)O)=C(C)C=C1 CSUZKPAQCFAMTO-UHFFFAOYSA-N 0.000 description 1
- LXPLEAMYRDJFKV-UHFFFAOYSA-N [C-]#[N+]C1=CC(OC2=NC(C3=CC=CC=C3)=NC=C2C(=O)OCC)=C(C)C=C1 Chemical compound [C-]#[N+]C1=CC(OC2=NC(C3=CC=CC=C3)=NC=C2C(=O)OCC)=C(C)C=C1 LXPLEAMYRDJFKV-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/34—One oxygen atom
Definitions
- the present invention relates to pyrimidinecarboxylic acid derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular diseases, in particular dyslipidaemias and arteriosclerosis.
- fibrates are the only therapy option for patients of these risk groups. They lower elevated triglyceride levels by 20-50%, reduce LDL-C by 10-15%, change the LDL particle size of atherogenic LDL of low density to less atherogenic LDL of normal density and increase the HDL concentration by 10-15%.
- Fibrates act as weak agonists of the peroxysome-proliferator-activated receptor (PPAR)-alpha ( Nature 1990, 347, 645-50).
- PPAR-alpha is a nuclear receptor which regulates the expression of target genes by binding to DNA sequences in the promoter range of these genes [also referred to as PPAR response elements (PPRE)].
- PPREs have been identified in a number of genes coding for proteins which regulate lipid metabolism.
- PPAR-alpha is highly expressed in the liver, and its activation leads inter alia to lower VLDL production/secretion and reduced apolipoprotein CIII (ApoCIII) synthesis. In contrast, the synthesis of apolipoprotein Al (ApoAl) is increased.
- a disadvantage of fibrates which have hitherto been approved is that their interaction with the receptor is only weak (EC 50 in the ⁇ M range), which in turn is responsible for the relatively small pharmacological effects described above.
- Ethyl 4-(2-methylphenoxy)-2-phenylpyrimidine-5-carboxylate and the corresponding carboxylic acid are described in WO 02/42280 as synthesis intermediates; a pharmacological activity of these compounds is not reported in this publication.
- U.S. Pat. No. 3,759,922, U.S. Pat. No. 3,850,931 and J. Heterocyclic Chem. 9 (6), 1347-54 (1972) describe certain 4-phenoxy-2-phenylpyrimidine-5-carboxylic acid derivatives as synthesis intermediates, some of which have a mydriatic or the activity of the central nervous system suppressing effect.
- WO 02/076438 claims inter alia pyrimidine derivatives as Flt 1 ligands for the treatment of cancer and various other disorders.
- the present invention provides compounds of the general formula (I)
- the present invention also provides compounds of the general formula (I) in which
- Compounds according to the invention are the compounds of the formula (I) and their salts, solvates and solvates of the salts, the compounds, comprised by formula (I), of the formulae mentioned below and their salts, solvates and solvates of the salts and the compounds, comprised by the formula (I), mentioned below as embodiments and their salts, solvates and solvates of the salts if the compounds, comprised by formula (I), mentioned below are not already salts, solvates and solvates of the salts.
- the compounds according to the invention can exist in stereoisomeric forms (enantiomers, diastereomers). Accordingly, the invention comprises the enantiomers or diastereomers and their respective mixtures. From such mixtures of enantiomers and/or diastereomers, it is possible to isolate the stereoisomerically uniform components in a known manner.
- the present invention comprises all tautomeric forms.
- preferred salts are physiologically acceptable salts of the compounds according to the invention.
- the invention also comprises salts which for their part are not suitable for pharmaceutical applications, but which can be used, for example, for isolating or purifying the compounds according to the invention.
- Physiologically acceptable salts of the compounds according to the invention include acid addition salts of mineral acids, carboxylic acids and sulphonic acids, for example salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid.
- hydrochloric acid hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid, benzenesulphonic acid, naphthalene disulphonic acid, acetic acid, trifluoroacetic acid, propionic acid, lactic acid, tartaric
- Physiologically acceptable salts of the compounds according to the invention also include salts of customary bases, such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salts (for example calcium salts and magnesium salts) and ammonium salts, derived from ammonia or organic amines having 1 to 16 carbon atoms, such as, by way of example and by way of preference, ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, ethylenediamine and N-methylpiperidine.
- customary bases such as, by way of example and by way of preference, alkali metal salts (for example sodium salts and potassium salts), alkaline earth metal salt
- solvates are those forms of the compounds according to the invention which, in solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a specific form of the solvates where the coordination is with water. In the context of the present invention, preferred solvates are hydrates.
- the present invention also comprises prodrugs of the compounds according to the invention.
- prodrugs includes compounds which for their part may be biologically active or inactive but which, during the time they spend in the body, are converted into compounds according to the invention (for example metabolically or hydrolytically).
- (C 1 -C 6 )-alkyl and (C 1 -C 4 )-alkyl represent a straight-chain or branched alkyl radical having 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is given to a straight-chain or branched alkyl radical having 1 to 4 carbon atoms.
- the following radicals may be mentioned by way of example and by way of preference: methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-ethylpropyl, n-pentyl and n-hexyl.
- (C 1 -C 6 )-alkoxy and (C 1 -C 4 )-alkoxy represent a straight-chain or branched alkoxy radical having 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms.
- the following radicals may be mentioned by way of example and by way of preference: methoxy, ethoxy, n-propoxy, isopropoxy and tert-butoxy.
- mono-(C 1 -C 6 )-alkylamino and mono-(C 1 -C 4 )-alkylamino represent an amino group having a straight-chain or branched alkyl substituent which has 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is given to a straight-chain or branched monoalkylamino radical having 1 to 4 carbon atoms.
- the following radicals may be mentioned by way of example and by way of preference: methylamino, ethylamino, n-propylamino, isopropylamino and tert-butylamino.
- di-(C 1 -C 6 )-alkylamino and di-(C 1 -C 4 )-alkylamino represent an amino group having two identical or different straight-chain or branched alkyl substituents which have in each case 1 to 6 and 1 to 4 carbon atoms, respectively. Preference is given to straight-chain or branched dialkylamino radicals having in each case 1 to 4 carbon atoms.
- radicals may be mentioned by way of example and by way of preference: N,N-dimethylamino, N,N-diethylamino, N-ethyl-N-methylamino, N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylamino, N-ethyl-N-n-pentylamino and N-n-hexyl-N-methylamino.
- a 4- to 7-membered heterocycle represents a saturated or partially unsaturated heterocycle having 4 to 7 ring atoms which contains a ring nitrogen atom and is attached via this ring nitrogen atom and may contain a further heteroatom from the group consisting of N, O, S, SO and SO 2 .
- radicals may be mentioned by way of example: pyrrolidinyl, pyrrolinyl, thiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepinyl and 1,4-diazepinyl. Preference is given to piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl and pyrrolidinyl.
- halogen includes fluorine, chlorine, bromine and iodine. Preference is given to chlorine or fluorine.
- radicals in the compounds according to the invention are substituted, the radicals can, unless specified otherwise, be mono- or polysubstituted.
- the meanings of radicals which occur more than once are independent of one another. Substitution with one, two or three identical or different substituents is preferred. Very particular preference is given to substitution with one substituent.
- radical definitions given in the respective combinations or preferred combinations of radicals may, independently of the particular given combination of radicals, also be replaced by any radical definitions of other combinations.
- the invention furthermore provides a process for preparing the compounds of the formula (I) according to the invention in which A represents O, characterized in that the compounds of the formula (II)
- R 3 , R 4 , R 5 and R 6 are each as defined above and
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , Z 1 and n are each as defined above, and these are converted by basic or acidic hydrolysis into the carboxylic acids of the formula (I-B)
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are each as defined above and the compounds of the formulae (I-A) and (I-B) are, if appropriate, converted into their solvates, salts and/or solvates of the salts using the appropriate (i) solvents and/or (ii) bases or acids.
- the compounds of the formula (II) can be prepared by initially reacting nitrile of the formula (IV)
- R 3 , R 4 , R 5 , R 6 and Z 1 are each as defined above, and then converting these in an inert solvent with the aid of a suitable halogenating agent, such as, for example, thionyl chloride, into the compounds of the formula (II).
- a suitable halogenating agent such as, for example, thionyl chloride
- Inert solvents for the process step (II)+(III) ⁇ (I-A) are, for example, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide, dimethyl sulphoxide, N,N′-dimethylpropyleneurea (DMPU), N-methylpyrrolidinone (NMP), pyridine or acetonitrile. It is also possible to use mixtures of the solvents mentioned.
- ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether
- hydrocarbons such as benzene, xylene, toluene,
- Suitable bases for process step (II)+(III) ⁇ (I-A) are customary inorganic bases. These include in particular alkali metal hydroxides, such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide, alkali metal carbonates or alkaline earth metal carbonates, such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate, or alkali metal hydrides, such as sodium or potassium hydride. Preference is given to potassium carbonate or sodium hydride.
- alkali metal hydroxides such as, for example, lithium hydroxide, sodium hydroxide or potassium hydroxide
- alkali metal carbonates or alkaline earth metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate or caesium carbonate
- alkali metal hydrides such as sodium or potassium hydride.
- potassium carbonate or sodium hydride Preference is given to potassium carbonate or sodium hydride.
- the base is employed in an amount of from 1 to 3 mol, preferably in an amount of from 1.2 to 2 mol, per mole of the compound of the formula (III).
- the reaction is generally carried out in a temperature range of from 0° C. to +100° C., preferably from +20° C. to +60° C.
- the reaction can be carried out at atmospheric, elevated or at reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
- the hydrolysis of the carboxylic acid in process steps (I-A) ⁇ (I-B) and (I-C) ⁇ (I-D) is carried out by customary methods by treating the esters in inert solvents with bases, where the salts initially formed are converted by treatment with acid into the free carboxylic acids.
- the ester cleavage is preferably carried out using acids.
- Suitable inert solvents for the hydrolysis of the carboxylic esters are water or organic solvents customary for ester cleavage. These preferably include alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers, such as diethyl ether, tetrahydrofuran, dioxane or glycol dimethyl ether, or other solvents, such as acetone, acetonitrile, dichloromethane, dimethylformamide or dimethyl sulphoxide. It is also possible to use mixtures of the solvents mentioned.
- Suitable bases for the ester hydrolysis are the customary inorganic bases. These preferably include alkali metal hydroxides or alkaline earth metal hydroxides such as, for example, sodium hydroxide, lithium hydroxide, potassium hydroxide or barium hydroxide, or alkali metal carbonates or alkaline earth metal carbonates, such as sodium carbonate, potassium carbonate or calcium carbonate. Particular preference is given to using sodium hydroxide or lithium hydroxide.
- Suitable acids for the ester cleavage are, in general, sulphuric acid, hydrogen chloride/hydrochloric acid, hydrogen bromide/hydrobromic acid, phosphoric acid, acetic acid, trifluoroacetic acid, toluenesulphonic acid, methanesulphonic acid or trifluoromethanesulphonic acid or mixtures thereof, if appropriate with addition of water.
- the ester cleavage is generally carried out in a temperature range of from 0° C. to +100° C., preferably from 0° C. to +40° C.
- the reaction can be carried out at atmospheric, elevated or at reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
- Suitable inert solvents for the process step (IV) ⁇ (V) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, 1,2-dichloroethane, trichloroethylene or chlorobenzene, or hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions. It is also possible to use mixtures of the solvents mentioned. Preference is given to toluene.
- the reaction partners ammonium chloride and trimethylaluminium used in the process step (IV) ⁇ (V) are in each case employed in an amount of from 2 to 4 mol, preferably in an amount of from 2 to 3 mol, per mole of the compound of the formula (IV).
- the reaction is generally carried out in a temperature range of from +20° C. to +150° C., preferably from +80° C. to +120° C.
- the reaction can be carried out at atmospheric, elevated or at reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
- Suitable inert solvents for the process step (V)+(VI) ⁇ (VII) are, for example, alcohols, such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether. It is also possible to use mixtures of the solvents mentioned. Preference is given to ethanol.
- Suitable bases for the process step (V)+(VI) ⁇ (VII) are in particular alkali metal alkoxides, such as sodium methoxide or potassium methoxide, sodium ethoxide or potassium ethoxide or potassium tert-butoxide. Preference is given to sodium ethoxide.
- the base is employed in an amount of from 2 to 3 mol, preferably in an amount of from 2 to 2.5 mol, per mole of the compound of the formula (V).
- the reaction is generally carried out in a temperature range of from +20° C. to +100° C., preferably from +50° C. to +80° C.
- the reaction can be carried out at atmospheric, elevated or at reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
- the halogenation and process step (VII) ⁇ (II) is preferably carried out with the aid of thionyl chloride or using para-toluenesulphonyl chloride or methanesulphonyl chloride, the latter in each case in the presence of a tertiary amine, such as, for example, triethylamine, N-methylmorpholine, N-methylpiperidine or N,N-diisopropylethylamine.
- a tertiary amine such as, for example, triethylamine, N-methylmorpholine, N-methylpiperidine or N,N-diisopropylethylamine.
- Suitable inert solvents for the process step (VII) ⁇ (II) are, for example, halogenated hydrocarbons, such as dichloromethane, trichloromethane, carbon tetrachloride, trichloroethane, tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers, such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbons, such as benzene, xylene, toluene, hexane, cyclohexane or mineral oil fractions, or other solvents, such as dimethylformamide or dimethyl sulphoxide. It is also possible to use mixtures of the solvents mentioned. Preference is given to dimethylformamide and dichloromethane.
- the reaction is generally carried out in a temperature range of from 0° C. to +60° C., preferably from 0° C. to +30° C.
- the reaction can be carried out at atmospheric, elevated or at reduced pressure (for example from 0.5 to 5 bar). In general, the reaction is carried out at atmospheric pressure.
- the invention furthermore provides a process for preparing the compounds of the formula (I) according to the invention in which A represents CH 2 , characterized in that either
- R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and n are each as defined above and the compounds of the formulae (I-C) and (I-D) are, if appropriate, converted into their solvates, salts and/or solvates of the salts using the appropriate (i) solvents and/or (ii) bases or acids.
- the compounds of the formulae (VIII), (IX) and (XI) are commercially available, known from the literature or can be prepared analogously to processes known from the literature.
- the compounds of the formulae (II) and (V) can be prepared as described above.
- the compounds according to the invention have useful pharmacological properties and can be used the prevention and treatment of disorders in humans and animals.
- the compounds according to the invention are highly effective PPAR-alpha modulators and as such are suitable in particular for the primary and/or secondary prevention and treatment of cardiovascular disorders caused by disturbances in fatty acid and glucose metabolism.
- cardiovascular disorders include dislipidaemias (hypercholesterolaemia, hypertriglyceridaemia, elevated concentrations of postprandial plasma triglycerides, hypoalphalipoproteinaemia, combined hyperlipidaemias), arteriosclerosis and metabolic disorders (metabolic syndrome, hyperglycaemia, insulin-dependent diabetes, non-insulin-dependent diabetes, gestation diabetes, hyperinsulinaemia, insulin resistance, glucose intolerance, obesity (adipositas) and late sequelae of diabetes, such as retinopathy, nephropathy and neuropathy).
- dislipidaemias hypercholesterolaemia, hypertriglyceridaemia, elevated concentrations of postprandial plasma triglycerides, hypoalphalipoproteinaemia, combined hyperlipidaemias
- Further independent risk factors for cardiovascular disorders which can be treated by the compounds according to the invention are high blood pressure, ischaemia, myocardial infaction, angina pectoris, cardiac insufficiency, myocardial insufficiency, restenosis, elevated levels of fibrinogen and of LDL of low density and also elevated concentrations of plasminogen activator inhibitor 1 (PAI-1).
- PAI-1 plasminogen activator inhibitor 1
- the compounds according to the invention can also be used for the treatment and/or prevention of micro- and macrovascular damage (vasculitis), reperfusion damage, arterial and venous thromboses, oedema, cancerous disorders (skin cancer, liposarcomas, carcinomas of the gastrointestinal tract, of the liver, of the pancreas, of the lung, of the kidney, of the urethra, of the prostate and of the genital tract), of disorders of the central nervous system and neurodegenerative disorders (strokes, Alzheimer's disease, Parkinson's disease, dementia, epilepsy, depressions, multiple sclerosis), of inflammatory disorders, immune disorders (Crohn's disease, ulcerative colitis, lupus erythematodes, rheumatoid arthritis, asthma), renal disorders (glomerulonephritis), disorders of the thyroid gland, disorders of the pancreas (pancreatitis), fibrosis of the liver, skin disorders (psoriasis, acne, eczema
- the activity of the compounds according to the invention can be examined, for example, in vitro by the transactivation assay described in the experimental section.
- the in vivo activity of the compounds according to the invention can be examined, for example, by the tests described in the experimental section.
- the present invention furthermore provides the use of the compounds according to the invention for the treatment and/or prevention of disorders, in particular the disorders mentioned above.
- the present invention also provides the use of the compounds according to the invention for preparing a medicament for the treatment and/or prevention of disorders, in particular the disorders mentioned above.
- the present invention also provides a method for the treatment and/or prevention of disorders, in particular the disorders mentioned above, using an effective amount of at least one compound according to the invention.
- the compounds according to the invention can be used alone or, if required, in combination with other active compounds.
- the present invention furthermore provides medicaments comprising at least one compound according to the invention and one or more further active compounds, in particlar for the treatment and/or prevention of the disorders mentioned above.
- Suitable active compounds for combinations are, by way of example and by way of preference: substances which modulate lipid metabolism, antidiabetics, hypertensive agents, perfusion-enhancing and/or antithrombotic agents and also antioxidants, chemokine receptor antagonists, p38-kinase inhibitor, NPY agonists, orexin agonists, anorectics, PAF-AH inhibitors, antiphlogistics (COX inhibitors, LTB 4 -receptor antagonists), analgesics (aspirin), antidepressants and other psychopharmaceuticals.
- the present invention provides in particular combinations comprising at least one of the compounds according to the invention and at least one lipid metabolism-modulating active compound, an antidiabetic, a hypertensive compound and/or antithrombotic agent.
- the compounds according to the invention can be combined with one or more
- Lipid metabolism-modifying active compounds are to be understood as meaning, preferably, compounds from the group of the HMG-CoA reductase inhibitors, squalene synthesis inhibitors, ACAT inhibitors, cholesterol absorptions inhibitors, MTP inhibitors, lipase inhibitors, thyroid hormones and/or thyroid mimetics, niacin receptor agonists, CETP inhibitors, PPAR-gamma agonists, PPAR-delta agonists, polymeric bile acid adsorbers, bile acid reabsorption inhibitors, antioxidants/radical scavengers and also the cannabinoid receptor 1 antagonists.
- the compounds according to the invention are administered in combination with an HMG-CoA reductase inhibitor from the class of the statins, such as, by way of example and by way of preference, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
- an HMG-CoA reductase inhibitor from the class of the statins, such as, by way of example and by way of preference, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, cerivastatin or pitavastatin.
- the compounds according to the invention are administered in combination with a squalene synthesis inhibitor, such as, by way of example and by way of preference, BMS-188494 or TAK-475.
- a squalene synthesis inhibitor such as, by way of example and by way of preference, BMS-188494 or TAK-475.
- the compounds according to the invention are administered in combination with an ACAT inhibitor, such as, by way of example and by way of preference, melinamide, pactimibe, eflucimibe or SMP-797.
- an ACAT inhibitor such as, by way of example and by way of preference, melinamide, pactimibe, eflucimibe or SMP-797.
- the compounds according to the invenetion are administered in combination with a cholesterol absorption inhibitor, such as, by way of example and by way of preference, ezetimibe, tiqueside or pamaqueside.
- a cholesterol absorption inhibitor such as, by way of example and by way of preference, ezetimibe, tiqueside or pamaqueside.
- the compounds according to the invention are administered in combination with an MTP inhibitor, such as, by way of example and by way of preference, implitapide or JTT-130.
- an MTP inhibitor such as, by way of example and by way of preference, implitapide or JTT-130.
- the compounds according to the invention are administered in combination with a lipase inhibitor, such as by way of example and by way of preference, orlistat.
- the compounds according to the invention are administered in combination with a thyroid hormone and/or thyroid mimetic, such as, by way of example and by way of preference, D-thyroxine or 3,5,3′-triiodothyronine (T3).
- a thyroid hormone and/or thyroid mimetic such as, by way of example and by way of preference, D-thyroxine or 3,5,3′-triiodothyronine (T3).
- the compounds according to the invention are administered in combination with an agonist of the niacin receptor, such as, by way of example and by way of preference, niacin, acipimox, acifran or radecol.
- an agonist of the niacin receptor such as, by way of example and by way of preference, niacin, acipimox, acifran or radecol.
- the compounds according to the invention are administered in combination with a CETP inhibitor, such as, by way of example and by way of preference, torcetrapib, JTT-705 or CETP vaccine (Avant).
- a CETP inhibitor such as, by way of example and by way of preference, torcetrapib, JTT-705 or CETP vaccine (Avant).
- the compounds according to the invention are administered in combination with a PPAR-gamma agonist, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
- a PPAR-gamma agonist such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
- the compounds according to the invention are administered in combination with a PPAR-delta agonist, such as, by way of example and by way of preference, GW-501516.
- a PPAR-delta agonist such as, by way of example and by way of preference, GW-501516.
- the compounds according to the invention are administered in combination with a polymeric bile acid adsorber, such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
- a polymeric bile acid adsorber such as, by way of example and by way of preference, cholestyramine, colestipol, colesolvam, CholestaGel or colestimide.
- the compounds according to the invention are administered in combination with a antioxidant/radical scavenger, such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
- a antioxidant/radical scavenger such as, by way of example and by way of preference, probucol, AGI-1067, BO-653 or AEOL-10150.
- the compounds according to the invention are administered in combination with a cannabinoid receptor 1 antagonist, such as, by way of example and by way of preference, rimonabant or SR-147778.
- a cannabinoid receptor 1 antagonist such as, by way of example and by way of preference, rimonabant or SR-147778.
- Antidiabetics are to be understood as meaning, preferably, insulin and insulin derivatives, and also orally effective hypoglycaemic acid compounds.
- insulin and insulin derivatives include both insulins of animal, human or biotechnological origin and also mixtures thereof.
- the orally effective hypoglycaemic active compounds preferably include sulphonylureas, biguanides, meglitinide derivatives, glucosidase inhibitors and PPAR-gamma agonists.
- the compounds according to the invention are administered in combination with insulin.
- the compounds according to the invention are administered in combination with a sulphonylurea, such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
- a sulphonylurea such as, by way of example and by way of preference, tolbutamide, glibenclamide, glimepiride, glipizide or gliclazide.
- the compounds according to the invention are administered in combination with a biguanide, such as, by way of example and by way of preference, metformin.
- a biguanide such as, by way of example and by way of preference, metformin.
- the compounds according to the invention are administered in combination with a meglitinide derivative, such as, by way of example and by way of preference, repaglinide or nateglinide.
- a meglitinide derivative such as, by way of example and by way of preference, repaglinide or nateglinide.
- the compounds according to the invention are administered in combination with a glucosidase inhibitor, such as, by way of example and by way of preference, miglitol or acarbose.
- a glucosidase inhibitor such as, by way of example and by way of preference, miglitol or acarbose.
- the compounds according to the invention are administered in combination with a PPAR-gamma agonist, for example from the class of the thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
- a PPAR-gamma agonist for example from the class of the thiazolidinediones, such as, by way of example and by way of preference, pioglitazone or rosiglitazone.
- hypertensive agents are preferably understood as meaning compounds from the group of the calcium antagonists, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, alpha-receptor blockers and diuretics.
- the compounds according to the invention are administered in combination with a calcium antagonist, such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
- a calcium antagonist such as, by way of example and by way of preference, nifedipine, amlodipine, verapamil or diltiazem.
- the compounds according to the invention are administered in combination with an angiotensin AII antagonist, such as, by way of example and by way of preference, losartan, valsartan, candesartan, embusartan or telmisartan.
- angiotensin AII antagonist such as, by way of example and by way of preference, losartan, valsartan, candesartan, embusartan or telmisartan.
- the compounds according to the invention are administered in combination with an ACE inhibitor, such as, by way of example and by way of preference, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
- an ACE inhibitor such as, by way of example and by way of preference, enalapril, captopril, ramipril, delapril, fosinopril, quinopril, perindopril or trandopril.
- the compounds according to the invention are administered in combination with a beta-receptor blocker, such as, by way of example and by way of preference, propranolol, atenolol, timolol, pindolol, alprenolol, oxprenolol, penbutolol, bupranolol, metipranolol, nadolol, mepindolol, carazalol, sotalol, metoprolol, betaxolol, celiprolol, bisoprolol, carteolol, esmolol, labetalol, carvedilol, adaprolol, landiolol, nebivolol, epanolol oder bucindolol.
- a beta-receptor blocker such as, by way of example and by way of preference, propranolol, atenolo
- the compounds according to the invention are administered in combination with an alpha-receptor blocker, such as, by way of example and by way of preference, prazosin.
- the compounds according to the invention are administered in combination with a diuretic, such as, by way of example and by way of preference, furosemide.
- a diuretic such as, by way of example and by way of preference, furosemide.
- the compounds according to the invention are administered in combination with antisympathotonics, such as reserpine, clonidine or alpha-methyldopa, with potassium channel-agonists, such as minoxidil, diazoxide, dihydralazine or hydralazine, or with nitrous oxide-releasing compounds, such as glycerol nitrate or sodium nitroprusside.
- antisympathotonics such as reserpine, clonidine or alpha-methyldopa
- potassium channel-agonists such as minoxidil, diazoxide, dihydralazine or hydralazine
- nitrous oxide-releasing compounds such as glycerol nitrate or sodium nitroprusside.
- Antithrombotics are to be understood as meaning, preferably, compounds from the group of the platelet aggregation inhibitors or the anticoagulants.
- the compounds according to the invention are administered in combination with a platelet aggregation inhibitor, such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamol.
- a platelet aggregation inhibitor such as, by way of example and by way of preference, aspirin, clopidogrel, ticlopidine or dipyridamol.
- the compounds according to the invention are administered in combination with a thrombin inhibitor, such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or clexane.
- a thrombin inhibitor such as, by way of example and by way of preference, ximelagatran, melagatran, bivalirudin or clexane.
- the compounds according to the invention are administered in combination with a GPIIb/IIIa antagonist, such as, by way of example and by way of preference, tirofiban or abciximab.
- a GPIIb/IIIa antagonist such as, by way of example and by way of preference, tirofiban or abciximab.
- the compounds according to the invention are administered in combination with a factor Xa inhibitor, such as, by way of example and by way of preference, DX-9065a, DPC 906, JTV 803, BAY 59-7939, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, SSR-126512 or SSR-128428.
- a factor Xa inhibitor such as, by way of example and by way of preference, DX-9065a, DPC 906, JTV 803, BAY 59-7939, DU-176b, fidexaban, razaxaban, fondaparinux, idraparinux, PMD-3112, YM-150, KFA-1982, EMD-503982, MCM-17, MLN-1021, SSR-126512 or SSR-128428.
- the compounds according to the invention are administered in combination with heparin or a low molecular weight (LMW) heparin derivative.
- LMW low molecular weight
- the compounds according to the invention are administered in combination with a vitamin K antagonist, such as, by way of example and by way of preference, coumarin.
- a vitamin K antagonist such as, by way of example and by way of preference, coumarin.
- the present invention furthermore provides medicaments comprising at least one compound according to the invention, usually together with one or more inert non-toxic pharmaceutically suitable auxiliaries, and their use for the purposes mentioned above.
- the compounds according to the invention can act systemically and/or locally.
- they can be administered in a suitable manner, such as, for example, orally, parenterally, pulmonally, nasally, sublingually, lingually, buccally, rectally, dermally, transdermally, conjunctivally, otically or as an implant or stent.
- the compounds according to the invention can be administered in suitable administration forms.
- Suitable for oral administration are administration forms which work in accordance with the prior art and release the compounds according to the invention rapidly and/or in modified form and which comprise the compounds according to the invention in crystalline and/or amorphicized and/or dissolved form, such as, for example, tablets (uncoated or coated tablets, for example with enteric coats or coats which dissolve in a delayed manner or are insoluble and which control the release of the compounds according to the invention), films/wafers or tablets which dissolve rapidly in the oral cavity, films/lyophilizates, capsules (for example hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.
- tablets uncoated or coated tablets, for example with enteric coats or coats which dissolve in a delayed manner or are insoluble and which control the release of the compounds according to the invention
- films/wafers or tablets which dissolve rapidly in the oral cavity
- films/lyophilizates capsules (for example hard or soft ge
- Parenteral administration may take place by circumventing a bioabsorption step (for example intravenously, intraarterially, intracardially, intraspinally or intralumbarly), or with bioabsorption (for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally).
- a bioabsorption step for example intravenously, intraarterially, intracardially, intraspinally or intralumbarly
- bioabsorption for example intramuscularly, subcutaneously, intracutaneously, percutaneously or intraperitoneally.
- Administration forms suitable for parenteral administration are inter alia preparations for injection or infusion in the form of solutions, suspensions, emulsions, lyophilizates or sterile powders.
- Suitable for other administration routes are, for example; medicaments suitable for inhalation (inter alia powder inhalers, nebulizers), nose drops, solutions or sprays, tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations to be administered to ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (for example plasters), milk, pastes, foams, powders for pouring, implants or stents.
- medicaments suitable for inhalation inter alia powder inhalers, nebulizers
- nose drops tablets to be administered lingually, sublingually or buccally, films/wafers or capsules, suppositories, preparations to be administered to ears or eyes, vaginal capsules, aqueous suspensions (lotions, shaking mixtures), lipophilic suspensions, ointments,
- the compounds according to the invention can be converted into the administration forms mentioned. This can be carried out in a manner known per se by mixing with inert non-toxic pharmaceutically suitable auxiliaries.
- auxiliaries include inter alia carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (for example liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecyl sulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (for example antioxidants, such as, for example, ascorbic acid), colorants (for example inorganic pigments, such as, for example, iron oxides), and flavour and/or odour corrigents.
- carriers for example microcrystalline cellulose, lactose, mannitol
- solvents for example liquid polyethylene glycols
- emulsifiers and dispersants or wetting agents for example
- the dosage is from about 0.01 to 100 mg/kg, preferably from about 0.01 to 20 mg/kg and very particularly preferably from 0.1 to 10 mg/kg of body weight.
- MS instrument type Micromass ZQ
- HPLC instrument type Waters Alliance 2795
- mobile phase A 1 l of water +0.5 ml of 50% strength formic acid
- mobile phase B 1 l of acetonitrile +0.5 ml of 50% strength formic acid
- flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
- UV detection 210 nm.
- MS instrument type Micromass ZQ
- HPLC instrument type HP 1100 Series
- UV DAD column: Phenomenex Synergi 2 ⁇ Hydro-RP Mercury 20 mm ⁇ 4 mm
- mobile phase A 1 l of water +0.5 ml of 50% strength formic acid
- mobile phase B 1 l of acetonitrile +0.5 ml of 50% formic acid
- flow rate 0.0 min 1 ml/min ⁇ 2.5 min/3.0 min/4.5 min 2 ml/min
- oven 50° C.
- UV detection 210 nm.
- Instrument Micromass Platform LCZ with HPLC Agilent Series 1100; column: Thermo HyPURITY Aquastar 3 ⁇ 50 mm ⁇ 2.1 mm; mobile phase A: 1 l of water +0.5 ml of 50% strength formic acid, mobile phase B: 1 l of acetonitrile +0.5 ml of 50% strength formic acid; gradient: 0.0min 100% A ⁇ 0.2 min 100% A ⁇ 2.9 min 30% A ⁇ 3.1 min 10% A ⁇ 5.5 min 10% A; oven: 50° C.; flow rate: 0.8 ml/min; UV detection: 210 nm.
- MS instrument type Micromass ZQ
- HPLC instrument type Waters Alliance 2795; column: Merck Chromolith SpeedROD RP-18e 50 mm ⁇ 4.6 mm
- mobile phase A 1 l of water +0.5 ml of 50% strength formic acid
- mobile phase B 1 l of acetonitrile +0.5 ml of 50% strength formic acid
- oven 35° C.
- flow rate 0.0 min 1.0 ml/min ⁇ 3.0 min 3.0 ml/min ⁇ 4.0 min 3.0 ml/min
- UV detection 210 nm.
- Instrument HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: 5 ml of HClO 4 (70% strength)/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 9 min 90% B ⁇ 9.2 min 2% B ⁇ 10 min 2% B; flow rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm.
- Instrument HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: 5 ml of HClO 4 (70% strength)/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 15 min 90% B ⁇ 15.2 min 2% B ⁇ 16 min 2% B; flow rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm.
- Instrument HP 1100 with DAD detection; column: Kromasil 100 RP-18, 60 mm ⁇ 2.1 mm, 3.5 ⁇ m; mobile phase A: 5 ml of HClO 4 (70% strength)/l of water, mobile phase B: acetonitrile; gradient: 0 min 2% B ⁇ 0.5 min 2% B ⁇ 4.5 min 90% B ⁇ 6.5 min 90% B ⁇ 6.7 min 2% B ⁇ 7.5 min 2% B; flow rate: 0.75 ml/min; column temperature: 30° C.; UV detection: 210 nm.
- MS instrument Micromass TOF (LCT); HPLC instrument: 2-column setup, Waters 2690; column: YMC-ODS-AQ, 50 mm ⁇ 4.6 mm, 3.0 ⁇ m; mobile phase A: water +0.1% formic acid, mobile phase B: acetonitrile +0.1% formic acid; gradient: 0.0 min 100% A ⁇ 0.2 min 95% A ⁇ 1.8 min 25% A ⁇ 1.9 min 10% A ⁇ 2.0 min 5% A ⁇ 3.2 min 5% A; oven: 40° C.; flow rate: 3.0 ml/min; UV detection: 210 nm.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 1A.
- Example 4A The title compound is prepared starting from Example 4A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 1A.
- Example 6A The title compound is prepared starting from Example 6A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 3A.
- Example 8A The title compound is prepared starting from Example 8A by a reaction sequence analogous to the one described in Example 1A.
- Example 9A The title compound is prepared starting from Example 9A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 3A.
- Example 11A The title compound is prepared starting from Example 11A by a reaction sequence analogous to the one described in Example 1A.
- Example 12A The title compound is prepared starting from Example 12A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 3A.
- Example 14A The title compound is prepared starting from Example 14A by a reaction sequence analogous to the one described in Example 1A.
- Example 15A The title compound is prepared starting from Example 15A by a reaction sequence analogous to the one described in Example 2A.
- Example 3A The title compound is prepared starting from Example 3A by a reaction sequence analogous to the one described in Example 1A.
- Example 17A The title compound is prepared starting from Example 17A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 1A.
- Example 19A The title compound is prepared starting from Example 19A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 3A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 1A.
- Example 22A The title compound is prepared starting from Example 22A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 3A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 1A.
- Example 25A The title compound is prepared starting from Example 25A by a reaction sequence analogous to the one described in Example 2A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 3A.
- the title compound is prepared by a reaction sequence analogous to the one described in Example 1A.
- Example 28A The title compound is prepared starting from Example 28A by a reaction sequence analogous to the one described in Example 2A.
- Example 2A The compound from Example 2A (100 ⁇ m) and the phenol derivative (100 ⁇ m) in DMF (500 ⁇ l) are combined, potassium carbonate (2 eq.) is then added and the mixture is stirred at room temperature overnight. 0.2 ml of ethanol and 0.2 ml of 1 N aqueous sodium hydroxide solution are then added, and the mixture is stirred at room temperature for 2 h. After addition of 0.1 ml of 2 N hydrochloric acid and dilution with DMSO, the mixture is directly purified by chromatography.
- Example 21 The title compound is prepared starting from Example 21 by a reaction sequence analogous to the one described in Example 18.
- Example 23 The title compound is prepared starting from Example 23 by a reaction sequence analogous to the one described in Example 18.
- Example 15 The title compound is prepared starting from Example 15 by a reaction sequence analogous to the one described in Example 18.
- Example 16 The title compound is prepared starting from Example 16 by a reaction sequence analogous to the one described in Example 18.
- Example 27 The title compound is prepared starting from Example 27 by a reaction sequence analogous to the one described in Example 18.
- Example 29 The title compound is prepared starting from Example 29 by a reaction sequence analogous to the one described in Example 18.
- Example 31 The title compound is prepared starting from Example 31 by a reaction sequence analogous to the one described in Example 18.
- Example 39 The title compound is prepared starting from Example 39 by a reaction sequence analogous to the one described in Example 18.
- Example 41 The title compound is prepared starting from Example 41 by a reaction sequence analogous to the one described in Example 18.
- Example 43 The title compound is prepared starting from Example 43 by a reaction sequence analogous to the one described in Example 18.
- Example 45 The title compound is prepared starting from Example 45 by a reaction sequence analogous to the one described in Example 18.
- Example 47 The title compound is prepared starting from Example 47 by a reaction sequence analogous to the one described in Example 18.
- Example 49 The title compound is prepared starting from Example 49 by a reaction sequence analogous to the one described in Example 18.
- a cellular assay is used to identify activators of the peroxysome proliferator-activated receptor alpha (PPAR-alpha).
- the GAL4-PPAR ⁇ expression construct contains the ligand binding domain of PPAR ⁇ (amino acids 167-468) which is PCR-amplified and cloned into the vector pcDNA3.1. This vector already contains the GAL4 DNA binding domain (amino acids 1-147) of the vector pFC2-dbd (Stratagene).
- the reporter construct which contains five copies of the GAL4 binding site upstream of a thymidine kinase promoter, expresses firefly luciferase ( Photinus pyralis ) following activation and binding of GAL4-PPAR ⁇ .
- CHO (Chinese hamster ovary) cells are sown in DMEM/F12 medium (BioWhittaker) supplemented by 10% foetal calf serum and 1% penicillin/streptomycin (GIBCO), at a cell density of 2 ⁇ 10 3 cells per well in a 384-well plate (Greiner). The cells are cultivated at 37° C. for 48 h and then stimulated. To this end, the substances to be tested are taken up in CHO-A-SFM medium (GIBCO) supplemented by 10% foetal calf serum and 1% penicillin/streptomycin (GIBCO) and added to the cells. After a stimulation period of 24 hours, the luciferase activity is measured using a video camera. The relative light units measured give, as a function of the substance concentration, a sigmoidal stimulation curve. The EC 50 values are calculated using the computer programme GraphPad PRISM (Version 3.02).
- the compounds according to the invention show EC 50 values of from 5 ⁇ M to 10 nM.
- the substances to be examined in vivo for their HDL-C-increasing activity are administered orally to male transgenic hApoAl mice.
- the animals have drinking water and feed ad libitum.
- the substances are administered orally once a day for 7 days.
- the test substances are dissolved in a solution of Solutol HS 15+ethanol+saline (0.9%) in a ratio of 1+1+8 or in a solution of Solutol HS 15+saline (0.9%) in a ratio of 2+8.
- the dissolved substances are administered in a volume of 10 ml/kg of body weight using a stomach tube. Animals which have been treated in exactly the same manner but have only been given the solvent (10 ml/kg of body weight), without test substance, serve as control group.
- a blood sample from each of the mice is taken by puncture of the retroorbital venous plexus, to determine ApoAl, serum cholesterol, HDL-C and serum triglycerides (TG) (zero value).
- TG serum triglycerides
- the test substance is administered for the first time to the animals. 24 hours after the final administration of substance (on the 8 th day after the beginning of treatment), a blood sample from each of the animals is again taken by puncture of the retroorbital venous plexus, to determine the same parameters.
- TG, cholesterol, HDL-C and human ApoAl are determined using a Cobas Integra 400 plus instrument (Cobas Integra, Roche Diagnostics GmbH, Mannheim, Germany) using the respective cassettes (TRIGL, CHOL2, HDL-C and APOAT).
- HDL-C is determined by gel filtration and post-column derivatization with MEGA cholesterol reagent (Merck KGaA) analogously to the method of Garber et al. [ J. Lipid Res. 41, 1020-1026 (2000)].
- the effect of the test substances on HDL-C, hApoAl and TG concentrations is determined by subtracting the value measured for the first blood sample (zero value) from the value measured for the second blood sample (after the treatment).
- the means of the differences of all HDL-C, hApoAl and TG values of a group are determined and compared with the mean of the differences of the control group.
- Statistical evaluation is carried out using Student's t-Test, after the variances have been checked for homogeneity.
- Substances which increase the HDL-C of the treated animals, compared to that of the control group, in a statistically significant (p ⁇ 0.05) manner by at least 20% or which lower TG in a statistically significant (p ⁇ 0.05) manner by at least 25% are considered to be pharmacologically effective.
- the compounds according to the invention can be converted into pharmaceutical preparations in the following ways:
- the mixture of the compound according to the invention, lactose and starch is granulated with a 5% strength solution (m/m) of the PVP in water.
- the granules are dried and then mixed with the magnesium stearate for 5 minutes.
- This mixture is compressed using a conventional tablet press (see above for the dimensions of the tablet).
- a compressive force of 15 kN is used as a guideline for the compression.
- 10 ml of oral suspension correspond to a single dose of 100 mg of the compound according to the invention.
- Rhodigel is suspended in ethanol, and the compound according to the invention is added to the suspension.
- the water is added while stirring.
- the mixture is stirred for about 6 h until the swelling of the Rhodigel is complete.
- the compound according to the invention is suspended in the mixture of polyethylene glycol and polysorbate with stirring. Stirring is continued until the compound according to the invention has dissolved completely.
- the compound according to the invention is, at a concentration below saturation solubility, dissolved in a physiologically acceptable solvent (for example isotonic saline, glucose solution 5% and/or PEG 400 solution 30%).
- a physiologically acceptable solvent for example isotonic saline, glucose solution 5% and/or PEG 400 solution 30%.
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Applications Claiming Priority (5)
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DE102005011447.4 | 2005-03-12 | ||
DE102005011447 | 2005-03-12 | ||
DE102005027150A DE102005027150A1 (de) | 2005-03-12 | 2005-06-11 | Pyrimidincarbonsäure-Derivate und ihre Verwendung |
DE102005027150.2 | 2005-06-11 | ||
PCT/EP2006/002054 WO2006097220A1 (de) | 2005-03-12 | 2006-03-07 | Pyrimidincarbonsäure-derivate und ihre verwendung |
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US (1) | US20080194598A1 (ru) |
EP (1) | EP1866289A1 (ru) |
JP (1) | JP2008533063A (ru) |
KR (1) | KR20070116876A (ru) |
AR (1) | AR055744A1 (ru) |
AU (1) | AU2006224812A1 (ru) |
BR (1) | BRPI0609207A2 (ru) |
CA (1) | CA2600681A1 (ru) |
DE (1) | DE102005027150A1 (ru) |
DO (1) | DOP2006000062A (ru) |
GT (1) | GT200600109A (ru) |
IL (1) | IL185895A0 (ru) |
MX (1) | MX2007011070A (ru) |
PE (1) | PE20061348A1 (ru) |
TW (1) | TW200724532A (ru) |
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Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
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US20100160386A1 (en) * | 2006-09-12 | 2010-06-24 | Bayer Schering Pharma Aktiengesellschaft | 4-phenoxy-nicotine acid derivatives and use thereof as ppar-modulators |
US20100234432A1 (en) * | 2007-09-07 | 2010-09-16 | Bayer Animal Health Gmbh | Substituted 6-phenylnicotinic acids and their use |
US20100298221A1 (en) * | 2006-09-12 | 2010-11-25 | Bayer Schering Pharma Aktiengesellschaft | 2-phenoxy nicotine acid derivative and use thereof |
WO2013063526A1 (en) | 2011-10-28 | 2013-05-02 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease |
WO2014144650A2 (en) | 2013-03-15 | 2014-09-18 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of primary sclerosing cholangitis and inflammatory bowel disease |
WO2014144485A1 (en) | 2013-03-15 | 2014-09-18 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease |
EP2995317A1 (en) | 2010-05-26 | 2016-03-16 | Satiogen Pharmaceuticals, Inc. | Bile acid recycling inhibitors and satiogens for treatment of diabetes, obesity, and inflammatory gastrointestinal conditions |
EP3266457A1 (en) | 2011-10-28 | 2018-01-10 | Lumena Pharmaceuticals LLC | Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases |
EP4241840A2 (en) | 2019-02-12 | 2023-09-13 | Mirum Pharmaceuticals, Inc. | Methods for treating cholestasis |
Families Citing this family (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA200707975B (en) | 2005-05-06 | 2008-11-26 | Du Pont | Method for preparation of optionally 2-substituted 1,6-dihydro-6-oxo-4-pyrimidinecarboxylic acids |
EP2591783A1 (en) * | 2007-04-13 | 2013-05-15 | Millennium Pharmaceuticals, Inc. | Combination anticoagulant therapy with a compound that acts as a factor Xa inhibitor |
DE102007061756A1 (de) | 2007-12-20 | 2009-06-25 | Bayer Healthcare Ag | Substituierte 4-Aminopyrimidin-5-carbonsäuren und ihre Verwendung |
DE102007061757A1 (de) | 2007-12-20 | 2009-06-25 | Bayer Healthcare Ag | Substituierte 2-Phenylpyrimidin-5-carbonsäuren und ihre Verwendung |
BR112013004882A2 (pt) | 2010-08-31 | 2016-05-03 | Snu R&Db Foundation | utilização de reprogramação fetal de agonista ppar delta |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CZ20013833A3 (cs) * | 1999-04-28 | 2002-02-13 | Aventis Pharma Deutschland Gmbh | Deriváty kyselin se dvěma arylovými zbytky jako ligandy receptorů PPAR a farmaceutické prostředky, které je obsahují |
YU39503A (sh) * | 2000-11-22 | 2006-05-25 | F. Hoffmann-La Roche Ag. | Derivati pirimidina |
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2005
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- 2006-03-07 WO PCT/EP2006/002054 patent/WO2006097220A1/de active Application Filing
- 2006-03-07 BR BRPI0609207-1A patent/BRPI0609207A2/pt not_active Application Discontinuation
- 2006-03-07 KR KR1020077023311A patent/KR20070116876A/ko not_active Application Discontinuation
- 2006-03-07 US US11/886,289 patent/US20080194598A1/en not_active Abandoned
- 2006-03-07 AU AU2006224812A patent/AU2006224812A1/en not_active Abandoned
- 2006-03-07 MX MX2007011070A patent/MX2007011070A/es not_active Application Discontinuation
- 2006-03-07 CA CA002600681A patent/CA2600681A1/en not_active Abandoned
- 2006-03-09 AR ARP060100888A patent/AR055744A1/es not_active Application Discontinuation
- 2006-03-10 TW TW095108034A patent/TW200724532A/zh unknown
- 2006-03-10 UY UY29416A patent/UY29416A1/es not_active Application Discontinuation
- 2006-03-10 PE PE2006000274A patent/PE20061348A1/es not_active Application Discontinuation
- 2006-03-10 DO DO2006000062A patent/DOP2006000062A/es unknown
- 2006-03-10 GT GT200600109A patent/GT200600109A/es unknown
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US20100234432A1 (en) * | 2007-09-07 | 2010-09-16 | Bayer Animal Health Gmbh | Substituted 6-phenylnicotinic acids and their use |
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US11376251B2 (en) | 2011-10-28 | 2022-07-05 | Shire Human Genetic Therapies, Inc. | Bile acid recycling inhibitors for treatment of pediatric cholestatic liver diseases |
WO2013063526A1 (en) | 2011-10-28 | 2013-05-02 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of hypercholemia and cholestatic liver disease |
WO2014144485A1 (en) | 2013-03-15 | 2014-09-18 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of barrett's esophagus and gastroesophageal reflux disease |
WO2014144650A2 (en) | 2013-03-15 | 2014-09-18 | Lumena Pharmaceuticals, Inc. | Bile acid recycling inhibitors for treatment of primary sclerosing cholangitis and inflammatory bowel disease |
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Also Published As
Publication number | Publication date |
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KR20070116876A (ko) | 2007-12-11 |
AR055744A1 (es) | 2007-09-05 |
DOP2006000062A (es) | 2006-12-15 |
CA2600681A1 (en) | 2006-09-21 |
JP2008533063A (ja) | 2008-08-21 |
TW200724532A (en) | 2007-07-01 |
IL185895A0 (en) | 2008-01-06 |
PE20061348A1 (es) | 2007-01-28 |
WO2006097220A1 (de) | 2006-09-21 |
MX2007011070A (es) | 2007-11-07 |
EP1866289A1 (de) | 2007-12-19 |
UY29416A1 (es) | 2006-10-31 |
BRPI0609207A2 (pt) | 2010-03-02 |
DE102005027150A1 (de) | 2006-09-28 |
AU2006224812A1 (en) | 2006-09-21 |
GT200600109A (es) | 2007-02-14 |
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